全文获取类型
收费全文 | 507篇 |
免费 | 48篇 |
国内免费 | 1篇 |
专业分类
556篇 |
出版年
2023年 | 3篇 |
2022年 | 5篇 |
2021年 | 18篇 |
2020年 | 9篇 |
2019年 | 10篇 |
2018年 | 12篇 |
2017年 | 8篇 |
2016年 | 10篇 |
2015年 | 39篇 |
2014年 | 38篇 |
2013年 | 46篇 |
2012年 | 46篇 |
2011年 | 35篇 |
2010年 | 27篇 |
2009年 | 25篇 |
2008年 | 19篇 |
2007年 | 31篇 |
2006年 | 28篇 |
2005年 | 21篇 |
2004年 | 15篇 |
2003年 | 26篇 |
2002年 | 13篇 |
2001年 | 7篇 |
2000年 | 6篇 |
1999年 | 8篇 |
1998年 | 6篇 |
1997年 | 5篇 |
1996年 | 3篇 |
1995年 | 4篇 |
1994年 | 3篇 |
1993年 | 3篇 |
1992年 | 3篇 |
1991年 | 1篇 |
1990年 | 2篇 |
1989年 | 2篇 |
1988年 | 3篇 |
1987年 | 1篇 |
1986年 | 2篇 |
1982年 | 2篇 |
1981年 | 4篇 |
1978年 | 1篇 |
1976年 | 1篇 |
1975年 | 1篇 |
1974年 | 1篇 |
1972年 | 1篇 |
1970年 | 1篇 |
1955年 | 1篇 |
排序方式: 共有556条查询结果,搜索用时 0 毫秒
31.
Differential effects of two growth inhibitory K vitamin analogs on cell cycle regulating proteins in human hepatoma cells 总被引:6,自引:0,他引:6
Markovits J Wang Z Carr BI Sun TP Mintz P Le Bret M Wu CW Wu FY 《Life sciences》2003,72(24):2769-2784
A comparison was made between two K vitamin analogs. Growth in vitro of Hep G2 hepatoma cells was inhibited both by Compound 5 (Cpd 5), a recently synthesized thioalkyl analog of vitamin K or 2-(2-mercaptoethanol)-3-methyl-1, 4-naphthoquinone, as well as by synthetic vitamin K3 (menadione). Using synchronized Hep G2 hepatoma cells, the actions of both Cpd 5 and vitamin K3 on cell cycle regulating proteins were examined. Cpd 5 decreased the levels of cyclin D1, Cdk4, p16, p21 and cyclin B1. By contrast, VK3 only decreased the level of cyclin D1, but had no effect on the levels of Cdk4, p16 or p21. Interestingly, both VK3 and VK2 increased the levels of p21. The naturally occurring K vitamins had little effect on cell growth and none on the cyclins or Cdks. Amounts and activity of the G1/S phase controlling Cdc25A were measured. We found that Cpd 5 directly inhibited both Cdc25A activity and its protein expression, whereas VK3 did not. Thus, the main effects of Cpd 5 were on G1 and S phase proteins, especially Cdk4 and Cdc25A amounts in contrast to VK3. Computer docking studies of Cpd 5 and VK3 to Cdc25A phosphatase showed three binding sites. In the best conformation, Cpd 5 was found to be closer to the enzyme active site than VK3. These findings show that Cpd 5 represents a new class of anticancer agent, being a protein tyrosine phosphatase (PTP) antagonist, that binds to Cdc25A with suppression of its activity. Tumors expressing high levels of oncogenic Cdc25A phosphatase may thus be susceptible to the growth inhibitory activities of this class of compound. 相似文献
32.
Masumoto J Dowds TA Schaner P Chen FF Ogura Y Li M Zhu L Katsuyama T Sagara J Taniguchi S Gumucio DL Núñez G Inohara N 《Biochemical and biophysical research communications》2003,303(1):69-73
ASC is a pro-apoptotic protein containing a pyrin domain (PD) and a caspase-recruitment domain (CARD). A previous study suggests that ASC interacts with Ipaf, a member of the Apaf-1/Nod1 protein family. However, the functional relevance of the interaction has not been determined. Here, we report that co-expression of ASC with Ipaf or oligomerization of ASC induces both apoptosis and NF-kappa B activation. Apoptosis induced through ASC was inhibited by a mutant form of Caspase-8 but not by that of Caspase-1. The PD of ASC physically interacted with Caspase-8 as well as with pyrin, the familial Mediterranean fever gene product. Caspase-8 deficiency rescued mouse fibroblasts from apoptosis induced by ASC oligomerization. Pyrin disrupted the interaction between ASC and Caspase-8, and inhibited both apoptosis and NF-kappa B activation induced by ASC. These findings suggest that ASC is a mediator of NF-kappa B activation and Caspase-8-dependent apoptosis in an Ipaf signaling pathway. 相似文献
33.
Catelani G Corsaro A D'Andrea F Mariani M Pistarà V Vittorino E 《Carbohydrate research》2003,338(22):2349-2358
2,6-di-O-benzyl- (9), 2-O-benzyl-3,4-O-isopropylidene- (19), and 2-O-benzyl-6-O-m-chlorobenzoyl-L-arabino-hexos-5-ulose (20) have been prepared using 4'-deoxy-4'-eno- and 6'-deoxy-5'-eno lactose dimethyl acetal derivatives 7 and 14 as key intermediates. The synthesis of enol ethers 7 and 14 has been performed with good yields by base-promoted elimination of acetone or p-toluenesulfonic acid from 2',6'-di-O-benzyl-, and 6'-O-p-toluenesulfonyl-2,3:5,6:3',4'-tri-O-isopropylidenelactose dimethyl acetal, respectively. The epoxidation with MCPBA of 7 and 14 in methanol or dichloromethane furnishes C-5'-methoxy and C-5'-m-chlorobenzoyloxy derivatives, easily transformed with good yields into L-arabino 5-ketoaldohexoses 9, 19 and 20. 相似文献
34.
Protein kinase C-associated kinase (PKK) mediates Bcl10-independent NF-kappa B activation induced by phorbol ester 总被引:1,自引:0,他引:1
Muto A Ruland J McAllister-Lucas LM Lucas PC Yamaoka S Chen FF Lin A Mak TW Núñez G Inohara N 《The Journal of biological chemistry》2002,277(35):31871-31876
Protein kinase C-associated kinase (PKK) is a recently described kinase of unknown function that was identified on the basis of its specific interaction with PKC beta. PKK contains N-terminal kinase and C-terminal ankyrin repeats domains linked to an intermediate region. Here we report that the kinase domain of PKK is highly homologous to that of two mediators of nuclear factor-kappa B (NF-kappa B) activation, RICK and RIP, but these related kinases have different C-terminal domains for binding to upstream factors. We find that expression of PKK, like RICK and RIP, induces NF-kappa B activation. Mutational analysis revealed that the kinase domain of PKK is essential for NF-kappa B activation, whereas replacement of serine residues in the putative activation loop did not affect the ability of PKK to activate NF-kappa B. A catalytic inactive PKK mutant inhibited NF-kappa B activation induced by phorbol ester and Ca(2+)-ionophore, but it did not block that mediated by tumor necrosis factor alpha, interleukin-1 beta, or Nod1. Inhibition of NF-kappa B activation by dominant negative PKK was reverted by co-expression of PKC beta I, suggesting a functional association between PKK and PKC beta I. PKK-mediated NF-kappa B activation required IKK alpha and IKK beta but not IKK gamma, the regulatory subunit of the IKK complex. Moreover, NF-kappa B activation induced by PKK was not inhibited by dominant negative Bimp1 and proceeded in the absence of Bcl10, two components of a recently described PKC signaling pathway. These results suggest that PKK is a member of the RICK/RIP family of kinases, which is involved in a PKC-activated NF-kappa B signaling pathway that is independent of Bcl10 and IKK gamma. 相似文献
35.
A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10) 总被引:17,自引:0,他引:17 下载免费PDF全文
Reid E Kloos M Ashley-Koch A Hughes L Bevan S Svenson IK Graham FL Gaskell PC Dearlove A Pericak-Vance MA Rubinsztein DC Marchuk DA 《American journal of human genetics》2002,71(5):1189-1194
We have identified a missense mutation in the motor domain of the neuronal kinesin heavy chain gene KIF5A, in a family with hereditary spastic paraplegia. The mutation occurs in the family in which the SPG10 locus was originally identified, at an invariant asparagine residue that, when mutated in orthologous kinesin heavy chain motor proteins, prevents stimulation of the motor ATPase by microtubule-binding. Mutation of kinesin orthologues in various species leads to phenotypes resembling hereditary spastic paraplegia. The conventional kinesin motor powers intracellular movement of membranous organelles and other macromolecular cargo from the neuronal cell body to the distal tip of the axon. This finding suggests that the underlying pathology of SPG10 and possibly of other forms of hereditary spastic paraplegia may involve perturbation of neuronal anterograde (or retrograde) axoplasmic flow, leading to axonal degeneration, especially in the longest axons of the central nervous system. 相似文献
36.
Srisawat C Houser-Scott F Bertrand E Xiao S Singer RH Engelke DR 《RNA (New York, N.Y.)》2002,8(10):1348-1360
The RNA-protein subunit assembly of nuclear RNase P was investigated by specific isolation and characterization of the precursor and mature forms of RNase P using an RNA affinity ligand. Pre-RNase P was as active in pre-tRNA cleavage as mature RNase P, although it contained only seven of the nine proteins found in mature RNase P. Pop3p and Rpr2p were not required for maturation of the RPR1 RNA subunit and virtually absent from pre-RNase P, implying that they are dispensable for pre-tRNA substrate recognition and cleavage. The RNase P subunit assembly is likely to occur in the nucleolus, where both precursor and mature forms of RNase P RNA are primarily localized. The results provide insight into assembly of nuclear RNase P, and suggest pre-tRNA substrate recognition is largely determined by the RNA subunit. 相似文献
37.
The sprouting of neurites from a neuron represents a highly specialized form of cellular morphogenesis that must involve coordinated changes in two major cellular processes at two membrane locations: reorganization of the cytoskeleton and redirection of membrane traffic from the trans-Golgi network to the plasma membrane of the growth tip. How exactly are these two processes linked and how is spatial and temporal coordination achieved at the first instance of neurite sprouting? Recent advances may have already revealed some, if not most of the pieces in the puzzle. We discuss below, with some extrapolations, of what has recently come to light, and what more is needed to construct a coherent picture. 相似文献
38.
39.
The tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is a potent lung carcinogen in the A/J mouse, and is believed to be a causative agent for human lung cancer. NNK requires metabolic activation by alpha-hydroxylation to exert its carcinogenic potential. The human P450, 2A6 is a catalyst of this reaction. There are two closely related enzymes in the mouse, P450 2A4 and 2A5, which differ from each other by only 11 amino acids. In the present study these two mouse P450s were expressed in Spodoptera frugiperda (Sf9) cells using recombinant baculovirus. The catalysis of NNK metabolism by Sf9 microsomal fractions containing either P450 2A4 or 2A5 was determined. Both enzymes catalyzed the alpha-hydroxylation of NNK but with strikingly different efficiencies and specificities. P450 2A5 preferentially catalyzed NNK methyl hydroxylation, while P450 2A4 preferentially catalyzed methylene hydroxylation. The KM and Vmax for the former were 1.5 microM and 4.0 nmol/min/nmol P450, respectively, and for the latter 3.9 mM and 190 nmol/min/nmol P450. The mouse coumarin 7-hydroxylase, P450 2A5 is a significantly better catalyst of NNK alpha-hydroxylation than is the closely related human enzyme, P450 2A6. 相似文献
40.
Brecht Devleesschauwer Juanita A. Haagsma Frederick J. Angulo David C. Bellinger Dana Cole D?rte D?pfer Aamir Fazil Eric M. Fèvre Herman J. Gibb Tine Hald Martyn D. Kirk Robin J. Lake Charline Maertens de Noordhout Colin D. Mathers Scott A. McDonald Sara M. Pires Niko Speybroeck M. Kate Thomas Paul R. Torgerson Felicia Wu Arie H. Havelaar Nicolas Praet 《PloS one》2015,10(12)